THIEME 106 Original Article

The Burden of Indirect Causes of Maternal Morbidity and Mortality in the Process of Obstetric Transition: A Cross-Sectional Multicenter Study Aimportânciadascausasindiretasdamorbidadee mortalidade maternas no processo de transição obstétrica: um estudo multicêntrico transversal

Jessica Fernandes Cirelli1 Fernanda Garanhani Surita1 Maria Laura Costa1 Mary Angela Parpinelli1 Samira Maerrawi Haddad1 José Guilherme Cecatti1

1 Department of Obsterics and Gynecology, School of Medical Address for correspondence Fernanda Garanhani Surita, Science, Universidade Estadual de Campinas, Campinas, Rua Alexander Fleming 101, 13083-881, Campinas, SP, Brazil São Paulo, SP, Brazil (e-mail: [email protected]).

Rev Bras Ginecol Obstet 2018;40:106–114.

Abstract Objective The aim of this study is to evaluate the burden of indirect causes of maternal morbidity/mortality in Brazil. Methods Secondary analysis of a multicenter cross-sectional study conducted in 27 referral obstetric units within the Brazilian Network for Surveillance of Severe Maternal Morbidity. Results A total of 82,388 women were surveilled: 9,555 women with severe maternal morbidity were included, and 942 (9.9%) of them had indirect causes of morbidity/ mortality. There was an increased risk of higher severity among the indirect causes group, which presented 7.56 times increased risk of (prevalence ratio [PR]: 7.56; 95% confidence interval [95%CI]: 4.99–11.45). The main indirect causes of maternal death were H1N1 influenza, sepsis, cancer and cardiovascular . Non-public antenatal care (PR: 2.52; 95%CI: 1.70–3.74), diabetes (PR: 1.90; 95%CI: 1.24–2.90), neoplasia (PR: 1.98; 95%CI: 1.25–3.14), kidney (PR: 1.99; 95%CI: 1.14–3.49), sickle cell anemia (PR: 2.50; 95%CI: 1.16–5.41) and drug addiction (PR: 1.98; 95%CI: 1.03–3.80) were independently associated with worse results in the indirect causes group. Some procedures for the management of severity were more common for the indirect causes group. Conclusion Indirect causes were present in less than 10% of the overall cases, but they represented over 40% of maternal deaths in the current study. Indirect causes of Keywords maternal morbidity/mortality were also responsible for an increased risk of higher ► maternal near-miss severity, and they were associated with worse maternal and perinatal outcomes. In ► maternal death middle-income countries there is a mix of indirect causes of maternal morbidity/ ► indirect causes mortality that points to some advances in the scale of obstetric transition, but also ► reveals the fragility of health systems.

received DOI https://doi.org/ Copyright © 2018 by Thieme Revinter June 27, 2017 10.1055/s-0038-1623511. Publicações Ltda, Rio de Janeiro, Brazil accepted ISSN 0100-7203. December 13, 2017 Burden of Indirect Causes of Maternal Morbidity and Mortality Cirelli et al. 107

Resumo Objetivo O objetivo deste estudo é avaliar a importância das causas indiretas da morbidade/mortalidade materna no Brasil. Métodos Análise secundária de um estudo transversal multicêntrico realizado em 27 unidades obstétricas de referência da Rede Brasileira de Vigilância da Morbidade Materna Grave. Resultados Um total de 82.388 mulheres foram avaliadas, sendo que 9.555 foram incluídas com morbidade materna grave, 942 (9,9%) delas com causas indiretas de morbidade/mortalidade. Houve risco aumentado de maior gravidade entre o grupo das causas indiretas, que apresentou risco de morte materna 7,56 vezes maior (razão de prevalência [RP]: 7.56; intervalo de confiança de 95% [IC95%]: 4.99–11.45). As principais causas indiretas de óbitos maternos foram a gripe H1N1, sepses, câncer e doença cardiovascular. Atenção pré-natal não pública (RP: 2,52; IC95%: 1,70–3,74), diabetes (RP: 1,90; IC95%: 1,24–2,90), neoplasia (RP: 1,98; IC95%: 1,25–3,14), doenças Renais (RP: 1,99; IC95%: 1,14–3,49), anemia falciforme (RP: 2,50; IC95%: 1,16–5,41) e toxicodependência (PR 1,98; IC95%: 1,03–3,80) foram associados independentemente com piores resultados no grupo de causas indiretas. Alguns procedimentos para o manejo da gravidade foram mais comuns para o grupo de causas indiretas. Conclusão As causas indiretas de morbidade mortalidade materna ocorreram em menos de 10% dos casos, mas foram responsáveis por mais de 40% das mortes maternas no presente estudo. As causas indiretas da morbidade mortalidade materna Palavras-chave também se relacionaram com maior gravidade, e estiveram associadas a piores ► near-miss materno resultados maternos e perinatais. Nos países de renda média, há uma combinação ► morte materna de causas indiretas de morbidade/mortalidade materna que apontam para alguns ► causas indiretas avanços na escala de transição obstétrica, mas também mostram a fragilidade dos ► saúde reprodutiva sistemas de saúde.

Introduction while altogether, including PLTC, we consider as severe Recent Sustainable Development Goals have been stablished maternal morbidity (SMM).1,3 by the United Nations (2015–2030), including thebroadgoal of The causes of maternal mortality/morbidity are classically “good health and wellbeing” for all. Based on the goals for the divided in three groups: direct obstetric causes (DOCs), previous period (2000–2015), there was an improvement in indirect obstetric causes (IOCs) or causes non-related to maternal health worldwide. However, the goal of significant .5 Direct obstetric causes are those occurring reduction in maternal mortality has not yet been reached, with a direct relationship to pregnancy, and are mostly on especially among low- and middle-income countries.1 This the spot because they are, by definition, avoidable.6 Indirect inequity represents a gender issue as well, regarding most of obstetric causes are defined as preexisting disorders or even the socially, psychologically and physically vulnerable popu- those aggravated by pregnancy.7 lations from poor settings. A way to consider maternal morbidity/mortality in differ- Maternal morbidity became a relevant outcome for under- ent settings is to use the concept of “obstetric transition.” standing maternal health, and it is defined as a continuum of This concept refers to the global trend in which a high rate of severity complicating a normal pregnancy.2,3 According to maternal morbidity/mortality with DOCs is being gradually specific criteria, women can experience a potentially life- replaced by lower rates, with a growing proportion of IOCs.8 threatening condition (PTLC) that can evolve to a state of organ High-income countries have started their transition over a dysfunction and/or failure.4 century ago, whereas middle- and low-income countries The World Health Organization (WHO) standardized the have only recently started it, and are still on the earlier definitions: PLTCs are severe maternal complications that stages of the process.8 There are five stages (I-V) in this include hemorrhage, hypertensive disorders, management of obstetric transition, and different moments of the phenom- severity and maternal near-miss (MNM), when a woman has enon present in different settings. Brazil is ranked in an almost died, but survived a given complication during preg- intermediate position, for the country is on stage III of this nancy, or the first 42 days post-partum.3 transition.8 Evaluating MNM cases might enable the understanding of The aim of the current study is to identify the burden of maternal death (MD) determinants.2,3 Maternal near-miss IOCs of maternal morbidity/mortality and to evaluate factors and MD characterize severe maternal outcomes (SMOs), associated with SMOs.

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Methods causes of maternal morbidity. Data onpregnancyoutcomes and perinatal results were also described, comparing both groups. This study is a secondary analysis with data obtained from Finally, Poisson multiple regression analysis was used to the database of the main study.1 All of the principles regu- identify the factors that were independently and significant- lating research on human beings, which were defined by the ly associated with SMOs (MD or MNM), compared with PLTCs Brazilian Health Council, as well as the Declaration of Hel- among the indirect causes of maternal morbidity. The ad-

sinki, were respected. Individual Informed Consent was justed prevalence ratio (PRadj) for the cluster design effect waived, since data were collected from medical records and for the remaining model variables as possible predictors, post-discharge or post-mortem, and no contact occurred with their respective 95% confidence intervals (95% CIs), with the research subjects. Local institutional review boards were presented. The statistical analysis was performed using and the National Committee on Ethics in Research approved the Statistical Package for the Social Sciences (SPSS, SPSS Inc., the study, under the letter of approval number 097/2009. Chicago, IL, US) software, version 17.0, the Stata (StataCorp, This study was funded by CNPq/DECIT (The Brazilian College Station, TX, US) software, version 7.0. The descriptive National Research Council and the Department of Science level was presented at 5% (95% confidence level), adjusted by and Technology of the Brazilian Ministry of Health) under the cluster design effect. grant number 402702/2008–5. All Strengthening the Reporting of Observational Studies We performed a secondary analysis focused on IOCs of in (STROBE) statement items for a prospective SMM within the Brazilian Network for Surveillance of Severe study were considered for the current study. Maternal Morbidity, a multicenter cross-sectional study implemented in 27 referral obstetric units in every region Results of Brazil, between 2009 and 2010, based on the WHO standardized criteria for SMM.5 Through a prospective sur- During the12-month period of the study, 82,388 women veillance, data were collected to identify cases of PLTC, MNM from 27 obstetric units were monitored, resulting in 82,144 and MD. Detailed information on the study methods has live births (LBs). Among these women, 9,555 met the criteria been previously published.5 for SMM (either PLTCs, MNM or MD). In this group, 942 had Briefly, the size of the sample was calculated considering an exclusively indirect cause of maternal morbidity: 713 that 75,000 deliveries should be surveyed to identify 750 cases were defined as PLTCs (75.7%), 170 as MNMs (18.0%) MNM cases, using an approximate theoretical incidence of 10 and 59 as MDs (6.3%) (►Table 1). Comparing the occurrence MNM cases per 1,000 deliveries as a basis for calculation.9,10 of severe outcomes between indirect and direct causes, there Data collection was performed by a trained research team, was an increased risk of higher severity among the exclu- considering all women admitted during pregnancy, childbirth sively indirect causes, which presented 7.56 times increased or the post-partum period with any of the criteria for severity risk of MD (PR: 7.56; 95%CI: 4.99–11.45). conditions defined by the WHO. The information retrieved Considering the health indicators (►Table 1) for indirect from medical charts were transferred into the OpenClinica causes of maternal morbidity, there is 1 MD for every 2.79 electronic platform (version 2.5.5, Waltham, MA, US) by the cases of MNM, while for the direct causes there is 1 MD for local coordinator from each participating center. every 8.29 MNM cases. The mortality rate –MD/(MNM þ MD) For data quality control, there was a strict personnel – was of 25.8% among the cases ofexclusively indirect causes of training for adequate data collection, chart review, and maternal morbidity, a rate significantly higher when com- feeding the database, with the implementation of an opera- pared with the direct underlying causes of morbidity, which tion manual and site visits for monitoring data control. have a mortality rate of 11.9%. Detailed typing and consistency checking by local and cen- All identified cases of MD due to indirect causes presented tral coordinators were also performed.9,10 an incidence of influenza H1N1 (30.5%), sepsis (20.3%), Data analysis for the current study approach consisted of a cancer (10.1%) and heart disease (10.1%). The remaining comparison of maternal and perinatal outcomes among cases were due other causes, or non-identified causes of women defined according to the underlying cause of mor- mortality (►Table 2). bidity as indirect or direct. The first group considered The risk of SMO for IOCs according to previous maternal exclusively IOCs of maternal morbidity, and the second one conditions increased among drug users (PR: 1.56; 95%CI: with any situation involving exclusive or associated DOCs of 1.05–2.032) and decreased among women with history of maternal morbidity or mortality. cardiac disease (PR: 0.40; 95%CI: 0.20–0.81) (►Table 2). Initially, the prevalence of PLTCs, MNM and MD was calcu- When evaluating maternal sociodemographic data and lated and compared between the two groups. We then consid- obstetric characteristics comparing the IOCs and DOCs of ered the health indicators of both groups: the MNM incidence maternal morbidity, there were very few significant differ- ratio (MNMIR), the severe maternal outcome ratio (SMOR ¼ ences among the groups, with increased risk for IOCs among MNM þ MD), the MNM to MD (MNM:MD) ratio, the mortality women with low weight (PR: 3.23; 95%CI: 1.70–6.14) and in index (MI) and the maternal mortality ratio (MMR), according private (PR: 2.04; 95%CI: 1.35–3.08). Considering to the WHO recommendations.3 We further assessed the socio- the perinatal results, Apgar scores < 7 at the 5th minute were demographic variables, previous morbid conditions, prenatal increased among cases of IOC (PR: 1.49; 95%CI: 1.01–2.21) care and obstetric complications, comparing direct and indirect when compared with cases of DOC (►Table 3).

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Table 1 Indicators of severe maternal morbidity according to the World Health Organization only for indirect and indirectobstetric causes

Total births¼ 82,838; total live births ¼ 82,144 Cause of SMM n ¼ 9555 Indirect causes n ¼ 942 Direct causes n ¼ 8613 n (%) n (%) PR(95%CI) SMM PLTCs 713 (75.7) 7932 (92.1) Ref. MNM 170 (18.0) 600 (7.0) 2.74 (2.00–3.74) MD 59 (6.3) 81 (0.9) 7.56 (4.99–11.45) Health Indicators MNMR/1,000 LBs 2.07 7.30 SMOR/1,000 LBs 2.79 8.29 MNM:MD 2.90 7.40 Mortality Index (%) 25.8 11.9 MMR/100,000 LBs 71.8 98.6

Abbreviations: 95%CI, 95% confidence interval; LBs, live births; MD, maternal death; MMR, maternal mortality ratio; MNM, maternal near-miss; MNMR, maternal near-miss ratio; MNM:MD, maternal near-miss to maternal death ratio; PLTCs, potentially life-threatening conditions; PR, prevalence ratio; Ref., reference; SMM, severe maternal morbidity; SMOR, severe maternal outcome ratio.

Asignificant proportion of the cases admitted due to IOCs avoidable causes of maternal mortality (mostly direct causes of maternal morbidity had severe complications throughout of mortality) are now understood as a phenomenon called pregnancy that did not lead to immediate delivery (37.8%) “obstetric transition.”8 Such changes are happening at differ- and was even discharged from the hospital, still pregnant, for ent countries, and are strongly connected to the governmen- further follow-up. In contrast, among the cases of DOC, only tal and the society’s improvements in implementing public 3.8% remained pregnant after an SMM event. Among the policies that promote social development and health aware- ones that delivered, most were through cesarean sections in ness.8 Brazil is currently on stage III of this obstetric transi- both groups (►Table 3). tion,withanMMRbetween299–50 MDs/100,000 LBs.8 Looking into the standard laboratory, clinical or management A systematic analysis was recently published with the criteria used to identify MNM, 36.2% of women with IOCs of intent of better understanding the worldwide causes of mor- maternal morbidity presented the combination of all 3 criteria, tality in order to improve quality of life and achieve more versus 24.1% in the DOC group (p ¼ 0.004; data not show). longevity among the populations. Data on mortality and its Among the procedures used as management criteria, intubation trends according to the sociodemographic measures of 195 not related to anesthesia (PR: 3.88; 95%CI: 3.06–4.93), venous countries between 1980 and 2015 were presented, and among central access (PR: 4.24; 95%CI: 3.23–5.56), admission to the the 249 studied causes of morbidity, there was a subgroup intensive care unit (PR: 2.46; 95%CI: 1.54–3.93) and hospitaliza- concerning maternal morbidity. The data confirm the decrease tion > 7 days (PR: 2.57; 95%CI: 1.74–3.81) were associated to in the absolute number of MDs, with hemorrhage still being IOCs of maternal morbidity, when compared with cases of DOCs the main cause of maternal mortality in the world.6 (data not show). There were a few limitations to our study. Unfortunately, it The multivariate analysis showed that exclusively indirect is impossible to define all complications as dichotomous direct causes, preexisting conditions, non-public health care cov- versus indirect causes of morbidity, and this must be pointed erage, diabetes, neoplasia, kidney disease and drug addiction out. We decided to consider pure indirect cases (called exclu- were independently associated with SMOs (►Table 4). sively indirect causes) of morbidity versus cases of mixed morbidity (direct or direct þ any indirect causes associated), Discussion thus enabling a better understanding of this scenario. To the best of our knowledge, there is only 1 other surveil- Our results reveal the burden of IOCs of maternal morbidity/ lance study, performed in 2014, that analyzed the IOCs of mortality among cases of severe morbidity in a Brazilian maternal morbidity/mortality in the context of MNM and MD population. In our settings, IOCs were responsible for only criteria; it is a secondary analysis of a WHO multicenter study.7 10% of the total cases of severe morbidity; however, they Other studies simply point out the associations between IOCs represented 40% of the deaths occurred, with a high mortali- and MD, like a recently published study from India that ty index (MI ¼ 25.8%). The MI correlates with the quality of included 39,704 LBs and 120 MDs, 27.5% of them due to care, indicating substandard care when above 20%.11 IOCs, mostly anemia.12 A review from Ghana with 30,269 Worldwide, IOCs of mortality are responsible for 1/4 LBs and 322 MDs showed that 22.4% of the cases were due maternal deaths.7 Gradual changes toward a decrease in to IOCs, with as the main cause.13 In Morocco, the

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Table 2 Causes of maternal death and estimated risk of sever maternal outcome for indirect obstetric causes according to previous maternal conditions

Causes of maternal death n (%) Influenza H1N1 18 (30.5) Sepsis 12 (20.3) Pulmonary 6 (10.1) Urinary 3 (5.0) Abdominal 3 (5.0) Cancer 6 (10.1) Heart disease 6 (10.1) AIDS 2 (3.3) Sickle cell disease 2 (3.3) Thromboembolic disease 2 (3.3) Erythematous systemic lupus 1 (1.6) Bone marrow aplasia 1 (1.6) Interstitial pneumonia 1 (1.6) Not identified 8 (13.5) Total 59 (100) Previous maternal conditions Indirect obstetric causes SMO n (%) PLTCs n (%) PR (95%CI) Cardiac diseases 14 (6.8) 119 (18.3) 0.40 (0.20–0.81) Other conditions 33 (16.1) 89 (13.7) 1.15 (0.80–1.66) 22 (10.7) 85 (13.1) 0.84 (0.52–1.35) Smoking 17 (8.3) 54 (8.3) 1.00 (0.72–1.38) Respiratory diseases 19 (9.3) 45 (6.9) 1.26 (0.73–2.20) Chronic hypertension 10 (4.9) 46 (7.1) 0.73 (0.42–1.29) Drug addiction 11 (5.4) 19 (2.9) 1.56 (1.05–2.032) Sickle cell disease – thalassemia 9 (4.4) 30 (4.6) 0.96 (0.63–1.48) Diabetes mellitus 8 (3.9) 27 (4.1) 0.95 (0.55–1.64) Neurologic diseases 3 (1.5) 31 (4.8) 0.36 (0.10–1.32) HIV-AIDS 9 (4.4) 18 (2.8) 1.41 (0.78–2.54) Thyroid diseases 6 (2.9) 18 (2.8) 1.05 (0.59–1.84) Renal diseases 8 (3.9) 13 (2.0) 1.61 (0.65–4.03) Neoplasia 7 (3.4) 11 (1.7) 1.65 (0.90–3.02) Collagenoses 4 (1.9) 12 (1.8) 1.04 (0.33–3.29) Low weight 3 (1.5) 6 (0.9) 1.40 (0.46–4.22) Total 229 713 806

Abbreviations: 95%CI, 95% confidence interval; PLTCs, potentially life-threatening conditions; PR, prevalence ratio; SMO, severe maternal outcome.

maternal death surveillance system (MDSS) has 313 registries, for SMO in low-income countries, and heart disease is the and 13.5% of them were classified as IOCs of MD, with heart main IOC of MD in high-income countries.8 It also shows that disease as the main cause of maternal mortality.14 In a women with any SMO related to an IOC have a higher risk of systematic review of 12 studies from 1980 to 2007, with developing obstetric complications, MNM and MD, as well as 9,750 MDs in high-income countries, 28.6% of the deaths worse perinatal outcomes.7 This information matches the were due to IOCs, and cardiovascular diseases were the main findings of our study. contributor cause.15 In the current analysis, it is important to consider that data The analysis regarding indirect causes published by the was collected during the 2009 H1N1 influenza pandemic WHO in 2014 reports that anemia is the most common cause season(H1N1pdm09),16 which began inMexico inMarch 2009,

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Table 3 Sample characteristics, termination of pregnancy and perinatal outcomes associated with an indirect obstetric cause of severe maternal morbidity

Sample characteristics Indirect cause Direct cause PR (95%CI) n(%) n(%) Age (years) 10–19 172 (18.3) 1,541 (17.9) 0.95 (0.79–1.15) 20–29 480 (51.0) 4,076 (47.3) Ref. 30–39 256 (27.2) 2,561 (29.7) 0.86 (0.69–1.08) 40–49 34 (3.6) 435 (5.1) 0.69 (0.46–1.03) Marital statusa With partner 446 (58.8) 3,827 (52.6) Ref. Single 312 (41.2) 3,454 (47.4) 0.79 (0.58–1.09) Schoolingb Primary 277 (45.2) 2,939 (46.6) 0.77 (0.54–1.11) High school 292 (47.6) 3,020 (47.9) 0.79 (0.54–1.15) University 44 (7.2) 351 (5.6) Ref. Ethnicityc White 386 (51.1) 2,645 (41.4) Ref. Non-white 370 (48.9) 3,738 (58.6) 0.71 (0.49–1.03) Obesityd Yes 107 (12.5) 1,882 (25.5) 0.45 (0.29–0.69) No 749 (87.5) 5,503 (74.5) Ref. Low weightd Yes 9 (1.1) 18 (0.2) 3.23 (1.70–6.14) No 847 (98.9) 7,367 (99.8) Ref. Paritye 0 399 (42.6) 4,177 (48.8) 1.17 (0.98–1.38) 1 241 (25.7) 2,129 (24.9) Ref. 2 296 (31.6) 2,251 (26.3) 1.14 (0.94–1.38) Abortionsf 0 709 (75.7) 6,659 (77.8) Ref. 1 227 (24.3) 1,896 (22.2) 1.11 (0.93–1.32) Perinataloutcomes Indirectcause Directcause PR(95%CI) n(%) n(%) End of pregnancyh Vaginal birth 128 (13.8) 2,010 (23.4) Ref. Cesarean section 394 (42.4) 5,760 (67.1) 1.07 (0.76–1.50) Abortion 56 (6.0) 489 (5.7) 1.72 (1.11–2.64) Still pregnant 351 (37.8) 326 (3.8) 7.93 (6.04–10.41) Gestational age at delivery (weeks)i < 28 57 (6.5) 552 (6.8) 1.49 (1.16–1.91) 28–33 88 (10.0) 1,336 (16.4) 0.98 (0.67–1.44) 34–36 98 (11.2) 1,682 (20.7) 0.88 (0.63–1.23) > 37 284 (32.3) 4,238 (52.1) Ref. (Continued)

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Table 3 (Continued)

Sample characteristics Indirect cause Direct cause PR (95%CI) n(%) n(%) Low birthweight (g)j < 2,500 171 (35.8) 2,978 (40.0) 0.85 (0.66–1.09) 2,500 306 (64.2) 4,468 (60.0) Ref. Apgar Score at 5 minutes < 7 26 (5.7) 270 (3.8) 1.49 (1.01–2.21) 7 431 (94.3) 6,898 (96.2) Ref. Vital condition at birthk Alive 474 (95.0) 7,259 (95.2) Ref. Stillbirth 25 (5.0) 363 (4.8) 1.05 (0.69–1.61) Neonatal outcomel Discharged 365 (78.2) 5,258 (75.3) Ref. Transferred 88 (18.8) 1,542 (22.1) 0.83 (0.64–1.08) Neonatal death 14 (3.0) 179 (2.6) 1.12 (0.72–1.74) Health carem Public 918 (97.8) 8,522 (99.0) Ref. Other 21 (2.2) 85 (1.0) 2.04 (1.35–3.08)

Abbreviations: 95%CI, 95% confidence interval; PR, prevalence ratio; Ref., reference. Notes: adjusted for the cluster design effect; still pregnant versus other grouped categories; missing information for: a1,516; b2,632; c2,416; d1,314; e62; f: 64; g2,098; h41; i545, j1,632; k1,930; l1434; m9.

Table 4 Variables associated to severe maternal outcomes (multiple regression analysis of a Poisson process)(n ¼ 5.608)

Variables PR 95%CI p Other preexisting conditions 2.48 1.91–3.21 < 0.001 Cause (exclusively indirect) 2.61 1.77–3.86 < 0.001 Financial coverage for hospitalization (other) 2.52 1.70–3.74 < 0.001 Obesity 0.58 0.45–0.75 < 0.001 Schooling (high school or higher) 0.68 0.57–0.82 < 0.001 Gestational age during the outcome (weeks) 0.96 0.94–0.98 < 0.002 Marital status (no partner) 0.52 0.35–0.77 0.002 Diabetes 1.90 1.24–2.90 0.005 Neoplasia 1.98 1.25–3.14 0.005 Kidney diseases 1.99 1.14–3.49 0.018 Sickle cell anemia 2.50 1.16–5.41 0.022 Drug addiction 1.98 1.03–3.80 0.042

Abbreviations: 95%CI, 95% confidence interval; PR, prevalence ratio. Notes: Analysis considering cluster design (center) multiple regression analysis of a Poisson process dependent variable: severe maternal outcomes (maternal near-miss þ maternal morbidity): 1/PLTC: 0; independent variable: “cause”: (exclusively indirect: 1; exclusively direct: 0), age (years), marital status (partner: 0; no partner: 1), schooling (up to elementary school: 0; high school or higher: 1), skin color (white: 0; other: 1), number of deliveries (0/ 1:1), number of abortions (0/ 1:1), number of prenatal visits (< 6:0/ 6:1), financial coverage for hospitalization (public: 0; other: 1), gestational age during the outcome (weeks), how pregnancy ended (vaginal delivery: 1; cesarean section; abortion; ectopic: 0),chronic hypertension(yes:1;no:0),obesity(yes:1;no:0),lowweight(yes:1;no:0),diabetes(yes:1;no:0),smoking(yes:1;no:0),heartdiseases(yes:1; no: 0), respiratory diseases (yes: 1; no: 0), kidney diseases (yes: 1; no: 0), sickle cell anemia (yes: 1; no: 0), HIV/AIDS (yes: 1; no: 0), thyroid diseases (yes: 1; no: 0), neurological diseases/epilepsy (yes: 1; no: 0), collagenosis (yes: 1; no: 0), and neoplasia (yes: 1; no: 0).

Rev Bras Ginecol Obstet Vol. 40 No. 3/2018 Burden of Indirect Causes of Maternal Morbidity and Mortality Cirelli et al. 113 and turned out to be the viral infection with the higher This finding may be a bias, because the present study does morbidity and mortality rates among pregnant and postpar- not have a control group of pregnant women at habitual risk, tum women in the last decades.17 which is one of its limitations. At the same time, low weight Maternal mortality related to sepsis is still high globally. It was associated with indirect causes of maternal morbidity, is estimated that 62,000 maternal deaths occur worldwide which can represent the impact of serious illnesses, such as every year with sepsis as the main cause.18 In high-income lupus, cancer and anemia. countries, the absolute risk of MD is relatively low (0.60 per Comparing the markers of clinical severity, it is possible to 100,000 LBs), but the risk of morbidity is substantially higher point out that women who were ill due to indirect causes of (20.9 per 100,000 LBs).1 When analyzing low-middle income maternal morbidity were more often submitted to intubation countries, these numbers become even more relevant, with a not related to anesthesia, again highlighting the severity of maternal mortality rate due to sepsis of 11.6%.18 There is respiratory diseases caused by the influenza H1N1 virus and little knowledge about the epidemiology of sepsis in Brazil their severe clinical complications, with the need of invasive regarding pregnancy and the postpartum period. In the respiratory support.16 Furthermore, the group of indirect current study, sepsis represented a total of 20.3% of maternal causes of maternal morbidity had more central venous access, mortality due to exclusively indirect causes. intensive care unit admission, and was hospitalized for periods Early identification and proper treatment are key to reduce longer than seven days, which also indicates higher clinical death rates due to infectious causes. Maternal mortality by severity. sepsis is directly related to the time it takes to recognize the In the group of indirect causes, more women have severity of the disease.19 On this note, there is a worldwide remained pregnant, even after treatment of the severe acute campaign toward awareness on timely and adequate diagnosis event that triggered hospitalization, when compared to the of sepsis.18,19 Besides sepsis, other worldwide relevant indi- group of direct causes of maternal morbidity. This indicates rect causes of maternal mortality are cancer and cardiovascu- that clinical complications early in pregnancy can often be lar diseases, which corroborate the findings of the present adequately controlled without interrupting the gestation, study. Possible hypotheses for the increase in these diseases and that might enhance the chances of a better perinatal among young women are worsening eating habits, increasing- result in such cases. However, the decision to maintain ly sedentary lifestyle, stress and life conditions that do not pregnancy is not always simple or straight-forward, and it prioritize health.20 depends on the individual’s response to the treatment. The number of women of reproductive age with previous Indirect causes of maternal morbidity and mortality will heart diseases has greatly increased over the past years due certainly increase among low- and middle-income coun- to the improvement in surgery, anesthesiology and clinical tries.23 In order to improve maternal and perinatal outcomes management of cardiac conditions.21,22 As a result, congeni- among these cases, there is a pressing need to strengthen tal heart defects currently represent 30% to 50% of all heart health services and to implement strategies to ascertain ade- diseases during .21,22 The current numbers in quate diagnosis and care of previous diseases among young Germany show 120,000 sick women, with an annual increase women, with adequate and referral centers of around 5,000.22 The evaluation of the prevalence of cases trained and qualified on emergency obstetric care.8,23 at different ages, comparing indirect and direct causes of maternal morbidity, presented no significant difference be- Conclusion tween both groups, with a predominance in women aged between 20 and 29 years. Regarding severity, a more in- Indirect causes of maternal morbidity/mortality were re- depth analysis within age groups has already been per- sponsible for less than 10% of the overall number of SMM formed in the same database, showing the impact of the cases; however, they represented over 40% of MDs. The main extremes of reproductive age on severe outcomes, with indirect causes of mortality were influenza H1N1, sepsis, increased MNM and maternal mortality ratios with older cancer and heart diseases. These women presented more age and also among adolescents. adverse perinatal outcomes. In order to promote better care Our findings also show a higher prevalence of fewer pre- for these women, a proper maternal health policy is neces- natal visits and increased private health care among cases of sary, with specific and timely interventions aiming to de- indirect causes of maternal morbidity. This might be an crease the impact of the indirect causes of morbidity among indication that complications in these women determine women with SMM. early hospital admission, and, for that reason, they have an impact on the total number of visits. Our numbers for private Contributors care were too low for us to draw any conclusions; however, The idea for the study and this specific analytical approach women with previous conditions are most likely the ones arose in a group discussion among all the authors. The concerned with their health, and are more prone to have analyses were planned by Cirelli JF, Surita FG and Cecatti private health insurance. JG. The first version of the manuscript was drafted by A paradoxical finding of our study was that obesity Cirelli JF, Surita FG and Costa ML. Subsequently, all appears as a protective factor for indirect causes. We have remaining authors complemented it with suggestions. a tendency of considering obesity as associated with indirect All authors contributed to the development of the study causes, perhaps due to chronic hypertension and diabetes. protocol and approved the final version of the manuscript.

Rev Bras Ginecol Obstet Vol. 40 No. 3/2018 114 Burden of Indirect Causes of Maternal Morbidity and Mortality Cirelli et al.

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